This grant will help initiate a major research program to undertake fundamental studies in the chemistry of recently discovered, biologically active antibiotics which are structurally unique and thus far unexplored. The proposed research involves studies directed toward the preparation of bicyclomycin, an antibiotic which demonstrates specific activity toward Gram-negative bacteria, and milbemycin beta 3, a novel macrocyclic antibiotic with highly potent pesticidal activity against insects which damage crops such as rice, corn, and citrus trees without phytotoxicity. Efforts toward bicyclomycin will seek to establish the 2-oxobicyclo(4.2.2) decane-7, 9-dione at a late stage of the synthesis by solvolytic ring closure. We will carefully examine the stability of this unique bicyclic system and the stereochemical features involved in its formation. Exhaustive studies of transformations of 2,5-diketopiperazines to their corresponding oxidation products to the relative stereochemistry of the hydroxylic functions on the carbon side chain have been solved by stereospecific preparation of an intermediate in which relative configurations have been confirmed by X-ray analysis. Our convergent approach toward milbemycin beta 3 has conveniently divided this macrocyclic lactone into three components. The synthesis of 1,7-dioxaspiro(5.5) systems has received very little attention. We suggest that the formation of these systems, and the associated stereochemitry, is a result of thermodynamic control. Our proposal will test this hypothesis. New methodology for formation of 1,3-diketones beginning with kinetically generated enolates will be examined. The two asymmetric components of milbemycin will be prepared optically active beginning in each case, with (-)(S)-citronellol.